The present invention describes a method for the preparation of asymmetric N,Nxe2x80x2-disubstituted cyclic ureas, which are useful as HIV protease inhibitors, through the selective acylation of substituted 1,4 diamino butanes.
U.S. Pat. No. 5,610,294 discloses cyclic urea compounds of formula (X) which are useful as HIV protease inhibitor compounds. 
U.S. Pat. No. 5,532,357 discloses methods for the preparation of compounds of formula (X), for example compound (X-a) via the isourea intermediate (XX). 
The isourea, (XX), can be used to prepare compounds of formula (X) which are unsymmetrical cyclic ureas.
A key intermediate in the synthesis of cyclic urea HIV protease inhibitors, such as (X-a), is the symmetrical diamine (I) (L. Rossano et al Tetrahedron. Lett., 1995, 36, 4967-4970). 
Methodology has been developed that allows for mono acylation of (I) enabling manipulation to unsymmetrical compounds such as (X-a). This mono acylation allows for the synthesis of unsymmetrical cyclic ureas by differentiating the symmetrical amines in (I). Additionally, mono acyl (I) can be prepared by first bis acylation of (I) followed by a selective hydrolysis to the same mono acyl derivative of (I).
T. Blacklock et al (J. Org. Chem, 1988, 53, 836-844) disclose the regioselective trifluoroacylation of L-lysine with ethyl trifluoroacetate in an aqueous sodium hydroxide medium using pH control to cause selective acylation. T. Shawe et al (Synthetic Communications, 1996, 26, 3633-3636) disclose the regiospecific trifluoroacyclation of N-methylethylenediamine by reaction with ethyl trifluoroacetate; although this chemistry uses ethyl trifluoroacetate as the acylating agent, it is distinguishing a primary amine over a secondary amine where one would expect there to be a difference in reactivity between the amines based on steric arguments. These references teach acylation of diamino compounds wherein the diamines are non equivalent sterically and chemically.
D Xu et al (Tetrahedron Letters, 1995, 36, 7357-7360) disclose the mono-trifluoro acylation of diamines, wherein acylation occurs rapidly with one equivalent of acylating agent in a polar solvent such as tetrahydrofuran at or below 0xc2x0 C. The authors describe mono acylation of a primary amine in a 1,2 diamine system wherein one amine acts as an internal base to activate the other amine. However, in the case of trans 1,2 diaminocyclohexane, a statistical mixture of diamine, mono-acylated and di-acylated material is obtained, indicating that no selectivity has occured. The authors postulate that this result is because one amine is not in close proximity to the other and so cannot promote acylation. Furthermore, the authors teach as the chain length between the amines increases, the degree of selectivity observed decreases.
The process of the present invention should not be amenable to selective acylation following the teachings of the literature, In the stereochemical configuration of diamine (I), the two primary amines have a trans configuration. Additionally, the diamines have a 1,4 relationship and thus there is an increase in the chain length between the amines. In addition, titration of (I) against hydrochloric acid reveals one inflection after two equivalents of acid have been added; because there is only one equivalence point, the two primary amines in (I) are not xe2x80x98communicatingxe2x80x99 with each other thus one amine cannot be acting as an internal base. Lastly, the two primary amines in (I) are not differentiated sterically.
Experimentally, following the teachings of the literature, in the process of the invention the acylation of diamine (I) results in very little selectivity. The selective trifluoroacylation of (I) occurs with an excess of ethyl trifluoroacetate in a non-polar solvent such as toluene at elevated temperatures; the use of polar solvents, such as tetrahydrofuran, tend to degrade the selectivity.
Despite the various methods for their preparation, there still exists a need for more efficient and cost effective methods for the preparation of unsymmetrical N,Nxe2x80x2-disubstututed cyclic urea HIV protease inhibitor compounds in high yield. The present invention provides improved processes for the synthesis of such compounds and processes for the synthesis of intermediates for their synthesis.
The diamine (I) is a key intermediate in the synthesis of unsymmetrical cyclic ureas that can be used as HIV protease inhibitors. This process allows the differentiation of the symmetrical primary amines in diamines of formula (I) in high yield. This process is suitable for large scale and is very volume efficient, providing excellent reactor through put in high yield and with low cost. The intermediates of the invention can be alkylated to give a wide range of unsymmetrical products which are useful as HIV protease inhibitors for the treatment of HIV infection. The dialkylated diamine intermediates of the invention provide starting materials, generally crystalline, suitable for large scale cyclization to cyclic ureas, which are, generally, crystalline.
The present invention provides an improved process for the cyclization of linear dialkylated diamines to cyclic ureas. Deleterious conditions of known processes are presented by an acid rearrangement mechanism, production to a high degree of byproduct, and the unsymmetrical amines of the substrate molecule. The present invention, through use of acid-base salt precipitates, unexpectedly improves upon the process by avoiding the acid rearrangement and minimizing the byproduct; therefore, resulting in a higher yield of cyclized urea in a process more suitable for large scale cyclization.
The present invention concerns an improved process for the preparation of asymmetric cyclic ureas as well as intermediates in the preparation of asymmetric cyclic ureas. In the process, a diamine of formula (I) is selectively monoacylated to give an asymmetric monoacylated diamine which can be converted into asymmetric intermediates, which can be further alkylated to give compounds which are useful as HIV protease inhibitors for the treatment of HIV infection. The invention allows for scalable preparation of a wide variety of asymmetrical cyclic ureas. The processes of the invention can be conducted on a kilogram scale, provide for high yields, and yield stable intermediates. 
In a first embodiment, the present invention provides a process for the preparation of compounds of formula (VI): 
wherein:
R7 is selected from the following:
C1-C8 alkyl substituted with 0-3 R11;
C2-C8 alkenyl substituted with 0-3 R11;
C2-C8 alkynyl substituted with 0-3 R11; and
a C3-C14 carbocyclic ring system substituted with 0-3 R11;
R10 is C1-C10 alkyl, benzyl, naphthylmethyl, 3,4-methylenedioxybenzyl, or C1-C4 alkyl substituted with phenyl wherein said phenyl is substituted with 0-3R10a;
R10a is C1-C4 alkyl, C1-C4 alkoxy, halo or cyano;
R11 is selected from one or more of the following:
C1-C4 alkoxy, C1-C4 alkyl, C2-C6 alkoxyalkyl, benzyl, phenethyl, phenoxy, benzyloxy, methylenedioxy, ethylenedioxy, C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, C3-C6 cycloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, 2-(1-morpholino)ethoxy;
xe2x80x94C(xe2x95x90O)R13, keto, cyano, nitro, xe2x80x94CH2NR13R14, xe2x80x94NR13R14, xe2x80x94CO2R13, xe2x80x94OC(xe2x95x90O)R13, xe2x80x94OR13, xe2x80x94OCH2CO2R13, xe2x80x94S(O)2R13, xe2x80x94C(xe2x95x90O)NR13R14, xe2x80x94NR14C(xe2x95x90O)R13, xe2x95x90NOR14, xe2x80x94NR14C(xe2x95x90O)OR14, xe2x80x94OC(xe2x95x90O)NR13R14, xe2x80x94NR13C(xe2x95x90O)NR13R14, xe2x80x94NR14SO2NR13R14, xe2x80x94NR14SO2R13, xe2x80x94SO2NR13R14;
C1-C4 alkyl substituted with xe2x80x94NR13R14; and
C3-C14 carbocyclic residue substituted with 0-3 R16;
R13 is independently selected from:
C1-C6 alkyl substituted with 0-3 R15;
C2-C6 alkenyl substituted with 0-3 R15; and
phenyl substituted with 0-3 R16;
R14 is independently selected from:
C1-C6 alkoxy, C2-C6 alkenyl, phenyl, benzyl, and
C1-C6 alkyl substituted with 0-3 C1-C4 alkoxy; or
R13 and R14 can alternatively join to form xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CH2CH2N(CH3)CH2CH2xe2x80x94, or xe2x80x94CH2CH2OCH2CH2xe2x80x94;
R15 is selected from one or more of the following:
C1-C4 alkoxy, C1-C4 alkyl, C2-C6 alkoxyalkyl, benzyl, phenethyl, phenoxy, benzyloxy, methylenedioxy, ethylenedioxy, C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, C3-C6 cycloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, 2-(1-morpholino)ethoxy;
xe2x80x94C(xe2x95x90O)R23, cyano, nitro, xe2x80x94CH2NR23R24, xe2x80x94NR23R24, xe2x80x94CO2R23, xe2x80x94OC(xe2x95x90O)R23, xe2x80x94OR23, xe2x80x94OCH2CO2R23, xe2x80x94S(O)2R23, xe2x80x94C(xe2x95x90O)NR23R24, xe2x80x94NR24C(xe2x95x90O)R23, xe2x95x90NOR24, xe2x80x94NR24C(xe2x95x90O)OR24, xe2x80x94OC(xe2x95x90O)NR23R24, xe2x80x94NR23C(xe2x95x90O)NR23R24, xe2x80x94NR24SO2NR23R24, xe2x80x94NR24SO2R23, xe2x80x94SO2NR23R24;
C1-C4 alkyl substituted with xe2x80x94NR23R24; and phenyl substituted with 0-3 R16;
R16 is selected from one or more of the following:
H, halogen, cyano, nitro, xe2x80x94CH2NR23R24, xe2x80x94NR23R24, xe2x80x94CO2R23, xe2x80x94OC(xe2x95x90O)R23, xe2x80x94OR23, xe2x80x94S(O)2R23, xe2x80x94C(xe2x95x90O)NR23R24, xe2x80x94NR24C(xe2x95x90O)R23, xe2x95x90NOR24, xe2x80x94NR24C(xe2x95x90O)OR24, xe2x80x94OC(xe2x95x90O)NR23R24, xe2x80x94NR23C(xe2x95x90O)NR23R24, xe2x80x94NR24SO2NR23R24, xe2x80x94NR24SO2R23, xe2x80x94SO2NR23R24;
C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkylmethyl, phenyl, benzyl, phenethyl, phenoxy, benzyloxy, C3-C6 cycloalkoxy, methylenedioxy, ethylenedioxy, C1-C4 alkoxycarbonyl, pyridylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, 2-(1-morpholino)ethoxy; and
C1-C4 alkyl substituted with xe2x80x94NR23R24;
R23 is C1-C4 alkyl substituted with 0-3 C1-C4 alkoxy;
R24 is C1-C4 alkyl substituted with 0-3 C1-C4 alkoxy; or
R23 and R24 can alternatively join to form xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CH2CH2N(CH3)CH2CH2xe2x80x94, or xe2x80x94CH2CH2OCH2CH2xe2x80x94; and
G taken together along with the oxygen atoms to which G is attached forms a group selected from:
xe2x80x94Oxe2x80x94C(xe2x80x94CH2CH2CH2CH2CH2xe2x80x94)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(CH2CH3)2xe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94C(CH3)(CH2CH3)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(CH2CH2CH2CH3)2xe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94C(CH3)(CH2CH(CH3)CH3)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH(phenyl)xe2x80x94Oxe2x80x94, xe2x80x94OCH2Oxe2x80x94,
xe2x80x94OC(CH3)2Oxe2x80x94, and xe2x80x94OC(OCH3)(CH2CH2CH3)Oxe2x80x94;
said process comprising:
(1) contacting a compound of formula (I): 
with an acylating agent of formula R1C(xe2x95x90O)R2;
wherein:
R1 is C1-C4 haloalkyl;
R2 is xe2x80x94OR3, xe2x80x94SR3, O-succinimide, or imidazolyl;
R3 is selected from the group:
C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne,
C1-C4 haloalkyl, C3-C10 cycloalkyl, pentafluorophenyl,
pyridin-2-yl, and phenyl substituted with 0-3 R3a;
R3a is selected from the group:
C1-C4 alkyl, C1-C4 alkoxy, halo, xe2x80x94CN, and xe2x80x94NO2;
to form a compound of formula (II). 
(2) contacting a compound of formula (II) with a compound of formula R7C(xe2x95x90O)H and subsequently contacting the imine product with a reducing agent to form a compound of formula (III): 
(3) contacting a compound of formula (III) with a suitable strong base at a temperature sufficient to form a compound of formula (IV): 
(4) contacting a compound of formula (IV) with 3-nitrile-4-fluoro-benzaldehyde and subsequently contacting the imine product with a reducing agent to form a compound of formula (V): 
(5) contacting a compound of formula (V) with phosgene in the presence of a second suitable base to form a compound of formula (VI).
In a preferred embodiment, the present invention provides a process for the preparation of a compound of formula (VI) wherein:
R7 is C1-C8 alkyl or phenyl; 
the reducing agent of step (2) is selected from sodium triacetoxy borohydride, sodium borohydride, pyridine/borane, lithium aluminium hydride, lithium borohydride, sodium cyanoborohydride, sodium amalgam, H2/Pd/C, H2/Pt/C, H2/Rh/C, and H2/Raney-Nickel;
the suitable strong base in step (3) is NaOH or KOH;
the reducing agent of step (4) is selected from sodium triacetoxy borohydride, sodium borohydride, pyridine/borane, lithium aluminium hydride, lithium borohydride, sodium cyanoborohydride, sodium amalgam, H2/Pd/C, H2/Pt/C, H2/Rh/C, and H2/Raney-Nickel; and
the suitable base in step (5) is selected from triethylamine, N,N-diisopropylethylamine, N,N-dimethyloctylamine, N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine, tris(hydroxymethyl)aminomethane, and 1,8-bis(dimethylamino)napthalene.
In a more preferred embodiment, the present invention provides a process for the preparation of a compound of formula (VI) wherein:
the reducing agent of step (2) is sodium triacetoxy borohydride or H2/Pt/C;
the suitable strong base in step (3) is NaOH or KOH;
the reducing agent of step (4) is sodium triacetoxy borohydride; and
the suitable base in step (5) is tris(hydroxymethyl)-aminomethane or N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine
In a second embodiment, the present invention provides a process for the preparation of a compound of formula (II): 
wherein:
R1 is C1-C4 haloalkyl;
R10 is C1-C10 alkyl, benzyl, naphthylmethyl, 3,4-methylenedioxybenzyl, or C1-C4 alkyl substituted with phenyl wherein said phenyl is substituted with 0-3 R10a;
R10a is C1-C4 alkyl, C1-C4 alkoxy, halo or cyano; and
G taken together along with the oxygen atoms to which G is attached forms a group selected from:
xe2x80x94Oxe2x80x94C(xe2x80x94CH2CH2CH2CH2CH2xe2x80x94)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(CH2CH3)2xe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94C(CH3)(CH2CH3)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(CH2CH2CH2CH3)2xe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94C(CH3)(CH2CH(CH3)CH3)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH(phenyl)xe2x80x94Oxe2x80x94, xe2x80x94OCH2Oxe2x80x94,
xe2x80x94OC(CH3)2Oxe2x80x94, and xe2x80x94OC(OCH3)(CH2CH2CH3)Oxe2x80x94;
the process, comprising:
(1) contacting a compound of formula (I): 
with an acylating agent of formula R1C(xe2x95x90O)R2;
wherein:
R2 is xe2x80x94OR3, xe2x80x94SR3, O-succinimide, or imidazolyl;
R3 is selected from the group:
C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne,
C1-C4 haloalkyl, C3-C10 cycloalkyl, pentafluorophenyl,
pyridin-2-yl, and phenyl substituted with 0-3 R3a;
R3a is selected from the group:
C1-C4 alkyl, C1-C4 alkoxy, halo, xe2x80x94CN, and xe2x80x94NO2;
to form a compound of formula (II).
In a preferred second embodiment, the present invention provides a process for the preparation of a compound of formula (II), wherein:
R1 is xe2x80x94CF3, xe2x80x94CF2CF3, xe2x80x94CF2CF2CF3, xe2x80x94CF2Cl, xe2x80x94CF2Br, xe2x80x94CCl3, xe2x80x94CBr3, or CH2F; and
R2 is xe2x80x94OCH3 or xe2x80x94OCH2CH3.
or wherein:
R1 is xe2x80x94CF3; and
R2 is xe2x80x94OCH3, xe2x80x94OCH2CH3, xe2x80x94OCH2CH2CH3, xe2x80x94OCH(CH3)2, xe2x80x94OCH2CHxe2x95x90CH2, xe2x80x94OCH2CF3, xe2x80x94SCH2CH3, xe2x80x94O-phenyl, xe2x80x94O-(4-nitrophenyl), or xe2x80x94Oxe2x80x94(2-pyridine).
In a more preferred second embodiment, the present invention provides a process for the preparation of a compound of formula (II) by contacting a compound of formula (II) with a suitable acid to form an acid addition salt.
In an even more preferred second embodiment, the present invention provides a process for the preparation of a compound of formula (II) wherein R1 is C1-C4 haloalkyl;
the process, comprising:
(1) contacting a compound of formula (I): 
with an acylating agent of formula R1C(xe2x95x90O)R2;
wherein:
R2 is xe2x80x94OR3, xe2x80x94SR3, O-succinimide, or imidazolyl;
R3 is selected from the group:
C1-C6 alkyl, C2-C6 alkene, C2-C6 alkyne,
C1-C4 haloalkyl, C3-C10 cycloalkyl, pentafluorophenyl,
pyridin-2-yl, and phenyl substituted with 0-3 R3a;
R3a is selected from the group:
C1-C4 alkyl, C1-C4 alkoxy, halo, xe2x80x94CN, and xe2x80x94NO2;
to form a compound of formula (II).
In a third embodiment, the present invention provides a process for the preparation of a compound of formula (II): 
wherein:
R1 is C1-C4 haloalkyl;
R10 is C1-C10 alkyl, benzyl, naphthylmethyl, 3,4-methylenedioxybenzyl, or C1-C4 alkyl substituted with phenyl wherein said phenyl is substituted with 0-3 R10a is C1-C4 alkyl, C1-C4 alkoxy, halo or cyano; and
G taken together along with the oxygen atoms to which G is attached forms a group selected from:
xe2x80x94C(xe2x80x94CH2CH2CH2CH2CH2xe2x80x94)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(CH2CH3)2xe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94C(CH3)(CH2CH3)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(CH2CH2CH2CH3)2xe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94C(CH3)(CH2CH(CH3)CH3)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH(phenyl)xe2x80x94Oxe2x80x94, xe2x80x94OCH2Oxe2x80x94,
xe2x80x94OC(CH3)2Oxe2x80x94, and xe2x80x94OC(OCH3)(CH2CH2CH3)Oxe2x80x94;
the process, comprising:
(1B) contacting a compound of formula (XI): 
with a suitable base to form a compound of formula (II).
In a preferred third embodiment, the present invention provides a process for the preparation of a compound of formula (II), wherein R1 is xe2x80x94CF3, xe2x80x94CF2CF3, xe2x80x94CF2CF2CF3, xe2x80x94CF2Cl, xe2x80x94CF2Br, xe2x80x94CCl3, xe2x80x94CBr3, or CH2F.
In a more preferred third embodiment, the present invention provides a process for the preparation of a compound of formula (II) wherein the suitable base in step (1B) is a hydroxide salt of sodium, potassium, lithium, calcium or magnesium; or a C1-C10 alkoxide salt of sodium, potassium, or lithium; or potassium t-butoxide in a mixture of tetrahydrofuran/methanol/water.
In an even more preferred third embodiment, the present invention provides a process for the preparation of a compound of formula (II) by further contacting a compound of formula (II) with a suitable acid to form an acid addition salt.
In an even more preferred embodiment, the present invention provides a process for the preparation of a compound of formula (II): 
wherein R1 is C1-C4 haloalkyl;
the process, comprising:
(1B) contacting a compound of formula (XI): 
with a suitable base to form a compound of formula (II).
In a fourth embodiment, the present invention provides a process for the preparation of a compound of formula (VI): 
wherein:
R7 is selected from the following:
C1-C8 alkyl substituted with 0-3 R11;
C2-C8 alkenyl substituted with 0-3 R11;
C2-C8 alkynyl substituted with 0-3 R11; and
a C3-C14 carbocyclic ring system substituted with 0-3 R11;
R10 is C1-C10 alkyl, benzyl, naphthylmethyl, 3,4-methylenedioxybenzyl, or C1-C4 alkyl substituted with phenyl wherein said phenyl is substituted with 0-3 R10a;
R10a is C1-C4 alkyl, C1-C4 alkoxy, halo or cyano;
R11 is selected from one or more of the following:
C1-C4 alkoxy, C1-C4 alkyl, C2-C6 alkoxyalkyl, benzyl, phenethyl, phenoxy, benzyloxy, methylenedioxy, ethylenedioxy, C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, C3-C6 cycloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, 2-(1-morpholino)ethoxy;
xe2x80x94C(xe2x95x90O)R13, keto, cyano, nitro, xe2x80x94CH2NR13R14, xe2x80x94NR13R14, xe2x80x94CO2R13,xe2x80x94OC(xe2x95x90O)R13, xe2x80x94OR13, xe2x80x94OCH2CO2R13, xe2x80x94S(O)2R13, xe2x80x94C(xe2x95x90O)NR13R14, xe2x80x94NR14C(xe2x95x90O)R13, xe2x95x90NOR14, xe2x80x94NR14C(xe2x95x90O)OR14, xe2x80x94OC(xe2x95x90O)NR13R14, xe2x80x94NR13C(xe2x95x90O)NR13R14, xe2x80x94NR14SO2NR13R14, xe2x80x94NR14SO2R13, xe2x80x94SO2NR13R14;
C1-C4 alkyl substituted with xe2x80x94NR13R14; and
C3-C14 carbocyclic residue substituted with 0-3 R16;
R13 is independently selected from:
C1-C6 alkyl substituted with 0-3 R15;
C2-C6 alkenyl substituted with 0-3 R15; and
phenyl substituted with 0-3 R16;
R14 is independently selected from:
C1-C6 alkoxy, C2-C6 alkenyl, phenyl, benzyl, and
C1-C6 alkyl substituted with 0-3 C1-C4 alkoxy; or
R13 and R14 can alternatively join to form xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CH2CH2N(CH3)CH2CH2xe2x80x94, or xe2x80x94CH2CH2OCH2CH2xe2x80x94;
R15 is selected from one or more of the following:
C1-C4 alkoxy, C1-C4 alkyl, C2-C6 alkoxyalkyl, benzyl, phenethyl, phenoxy, benzyloxy, methylenedioxy, ethylenedioxy, C2-C4 alkenyl, C3-C10 cycloalkyl, C3-C6 cycloalkylmethyl, C3-C6 cycloalkoxy, C1-C4 alkoxycarbonyl, C1-C4 alkylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, 2-(1-morpholino)ethoxy;
xe2x80x94C(xe2x95x90O)R23, cyano, nitro, xe2x80x94CH2NR23R24, xe2x80x94NR23R24, xe2x80x94CO2R23, xe2x80x94OC(xe2x95x90O)R23, xe2x80x94OR23, xe2x80x94OCH2CO2R23, xe2x80x94S(O)2R23, xe2x80x94C(xe2x95x90O)NR23R24, xe2x80x94NR24C(xe2x95x90O)R23, xe2x95x90NOR24, xe2x80x94NR24C(xe2x95x90O)OR24, xe2x80x94OC(xe2x95x90O)NR23R24, xe2x80x94NR23C(xe2x95x90O)NR23R24, xe2x80x94NR24SO2NR23R24, xe2x80x94NR24SO2R23, xe2x80x94SO2NR23R24;
C1-C4 alkyl substituted with xe2x80x94NR23R24; and
phenyl substituted with 0-3 R16;
R16 is selected from one or more of the following:
H, halogen, cyano, nitro, xe2x80x94CH2NR23R24, xe2x80x94NR23R24, xe2x80x94CO2R23, xe2x80x94OC(xe2x95x90O)R23, xe2x80x94OR23, xe2x80x94S(O)2R23, xe2x80x94C(xe2x95x90O)NR23R24, xe2x80x94NR24C(xe2x95x90O)R23, xe2x95x90NOR24, xe2x80x94NR24C(xe2x95x90O)OR24, xe2x80x94OC(xe2x95x90O)NR23R24, xe2x80x94NR23C(xe2x80x94xe2x95x90O)NR23R24, xe2x80x94NR24SO2NR23R24, xe2x80x94NR24SO2R23, xe2x80x94SO2NR23R24;
C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkylmethyl, phenyl, benzyl, phenethyl, phenoxy, benzyloxy, C3-C6 cycloalkoxy, methylenedioxy, ethylenedioxy, C1-C4 alkoxycarbonyl, pyridylcarbonyloxy, C1-C4 alkylcarbonyl, C1-C4 alkylcarbonylamino, 2-(1-morpholino)ethoxy; and
C1-C4 alkyl substituted with xe2x80x94NR23R24;
R23 is C1-C4 alkyl substituted with 0-3 C1-C4 alkoxy;
R24 is C1-C4 alkyl substituted with 0-3 C1-C4 alkoxy; or
R23 and R24 can alternatively join to form xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)5xe2x80x94, xe2x80x94CH2CH2N(CH3)CH2CH2xe2x80x94, or xe2x80x94CH2CH2OCH2CH2xe2x80x94; and
G taken together along with the oxygen atoms to which G is attached forms a group selected from: xe2x80x94Oxe2x80x94C(xe2x80x94CH2CH2CH2CH2CH2xe2x80x94)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(CH2CH3)2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(CH3)(CH2CH3)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(CH2CH2CH2CH3)2xe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94C(CH3)(CH2CH(CH3)CH3)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH(phenyl)xe2x80x94Oxe2x80x94, xe2x80x94OCH2Oxe2x80x94,
xe2x80x94OC(CH3)2Oxe2x80x94, and xe2x80x94OC(OCH3)(CH2CH2CH3)Oxe2x80x94;
said process comprising:
(5) contacting a compound of formula (V): 
with a cyclizing agent selected from phosgene, diphosgene, and triphosgene, in the presence of a suitable base to form a compound of formula (VI).
In a preferred fourth embodiment, the present invention provides a process for the preparation of a compound of formula (VI) wherein R7 is C1-C8 alkyl or phenyl; said process comprising:
(5) contacting a compound of formula (V) with a cyclizing agent selected from phosgene, diphosgene, and triphosgene, in the presence of a suitable base to form a compound of formula (VI).
In a more preferred fourth embodiment, the present invention provides a process for the preparation of a compound of formula (VI) wherein the suitable base in step (5) is selected from triethylamine, N,N-diisopropylethylamine, N,N-dimethyloctylamine, N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine, tris(hydroxymethyl)aminomethane, and 1,8-bis(dimethylamino)napthalene.
In a fifth embodiment, the present invention provides compounds of formula 
and acid addition salts thereof, wherein:
R1 is xe2x80x94CF3, xe2x80x94CF2CF3, xe2x80x94CF2CF2CF3, xe2x80x94CF2Cl, xe2x80x94CF2Br, xe2x80x94CCl3, xe2x80x94CBr3 or CH2F; and
R7 is propyl or phenyl.
In a sixth embodiment, the present invention provides compounds of formula 
and acid addition salts thereof, wherein:
R1 is xe2x80x94CF3, xe2x80x94CF2CF3, xe2x80x94CF2CF2CF3, xe2x80x94CF2Cl, xe2x80x94CF2Br, xe2x80x94CCl3, xe2x80x94CBr3 or CH2F; and
R7 is propyl or phenyl.
In a seventh embodiment, the present invention provides compounds of formula 
and acid addition salts thereof, wherein R7 is propyl or phenyl.
In a eighth embodiment, the present invention provides compounds of formula 
and acid addition salts thereof wherein R7 is propyl or phenyl.
In a ninth embodiment, the present invention provides a process for the preparation of a compound of formula (X): 
comprising contacting a compound of formula (VI) with hydrazine, or a hydrazine equivalent, under conditions sufficient to form a compound of formula (X), or a pharmaceutically acceptable salt form thereof; wherein a condition sufficient to form a compound of formula (X) comprises:
(a) removing the diol protecting group G of formula (VI) before contacting a compound of formula (VI) with hydrazine, or a hydrazine equivalent; or
(b) removing the diol protecting group G of formula (VI) after contacting a compound of formula (VI) with hydrazine, or a hydrazine equivalent.
The reactions of the synthetic methods claimed herein are carried out in suitable solvents which may be readily selected by one of skill in the art of organic synthesis, said suitable solvents generally being any solvent which is substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which may range from the solvent""s freezing temperature to the solvent""s boiling temperature. A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step may be selected.
As used herein, suitable aprotic solvents include, by way of example and without limitation, ether solvents and hydrocarbon solvents. Suitable ether solvents include tetrahydrofuran, diethyl ether, diethoxymethane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, or t-butyl methyl ether. Suitable hydrocarbon solvents include: butane, pentane, hexane, heptane, octane, nonane, decane, cyclohexane, cycloheptane, methylcyclohexane; as well as aryl hydrocarbon solvents.
As used herein, suitable acetate solvents include methyl, ethyl, propyl and iso-propyl acetate.
As used herein, suitable halogenated sol anded to chlorobutane, methylene chloride, chloroform, dichloroethane, and carbon tetrachloride.
As used herein, suitable aryl solvents include toluene, benzene, o-xylene, m-xylene and p-xylene.
As used herein the term xe2x80x9cacylating agentxe2x80x9d or xe2x80x9cstrongly electrophilic acylating agentxe2x80x9d refers to any agent which can acylate a primary amine. xe2x80x9cAcylating agentxe2x80x9d generally refers to agents of formula R1C(xe2x95x90O)R2 which can selectively acylate one primary amine in the presence of a second primary amine. Examples of acylating agents include R2 as an alkoxy or phenoxy group and R1 as a C1-C4 haloalkyl group, such as CF3, CF2CF3, CF2CF2CF3, CF2Cl, CF2Br, CCl3, CBr3, or CH2F. xe2x80x9cStrongly electrophilic acylating agentxe2x80x9d generally refers to agents which can nonselectively acylate two primary amines in one molecule, for example anhydrides of formula, R1(CO)O(CO)R1, or R1 substituted acid halides, eg. R1C(xe2x95x90O)Cl, but may also include acylating agents of formula R1C(xe2x95x90O)R2 depending on the reaction conditions as determined by one of skill in the art to synthesize a compound of formula (II). Examples of strongly electrophilic acylating agents are where R1 is a C1-C3 haloalkyl, such as CF3, CF2CF3, CF2CF2CF3, CF2Cl, CF2Br, CCl3, CBr3, or CH2F.
As used herein, the term xe2x80x9creducing agentxe2x80x9d refers to any agent which can effect the reduction of an imine to an amine without effecting a chemical change on any other substitutents on the diamine substrate. Examples of reducing agents include hydrogen metal catalysts, chemical reducing agents, and catalytic transfer hydrogenation. Examples of hydrogen metal catalysts include, but are not limited to, Pd/C, Pt/C, Rh/C, and Raney-Nickel. Examples of chemical reducing agents include, but are not limited to, sodium triacetoxy borohydride, sodium borohydride, pyridine/borane, lithium aluminium hydride, lithium borohydride, sodium cyanoborohydride, and sodium amalgam.
As used herein, the term xe2x80x9chydrolyzing agentxe2x80x9d means a reagent capable of generating sufficient hydroxide ion in solution to remove the acyl group from a compound of formula (III). Examples of suitable hydrolyzing agents include but are not limited to sodium hydroxide in methanol, potassium hydroxide in isopropanol and potassium hydroxide in n-butanol.
As used herein, the term xe2x80x9ccyclizing agentxe2x80x9d means a reagent that can effect the formation of a cyclic urea from the diamine of formula (V). Examples of suitable cyclizing agents include but are not limited to phosgene, diphosgene, triphosgene, 1,1xe2x80x2-carbonyl diimidazole, phenyl chloroformate, 4-nitro-phenyl chloroformate, phenyl tetrazoylformate, oxalyl chloride, N,Nxe2x80x2-disuccinimidyl carbonate, trichloromethyl chloroformate, C1-C4 dialkyl carbonate, ethylene carbonate, vinylene carbonate, and 2(S),3 pyridinediyl carbonate.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having one to twelve carbon atoms; for example, C1-C4 alkyl includes methyl, ethyl, n-propyl, 1-propyl, n-butyl, 1-butyl, s-butyl, and t-butyl. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl and the like; and xe2x80x9calkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, butynyl and the like.
As used herein, xe2x80x9ccycloalkylxe2x80x9d is intended to include saturated ring groups, including mono-, bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and cyclooctyl.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclicxe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo.
As used herein xe2x80x9chaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen. For example, C1-C4 haloalkyl includes, but is not limited to, CF3, CF2CF3, CF2CF2CF3, CF2CF2CF2CF3, CF2Cl, CF2Br, CCl3, CBr3, CH2F, CH2CF3, and the like.
As used herein xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. For example C1-C4 alkoxy includes methoxy, ethoxy, propoxy and butoxy. As used herein xe2x80x9ccycloalkoxyxe2x80x9d represents a cycloalkyl group of indicated number of carbon atoms attached through an oxygen bridge. For example C3-C6 cycloalkoxy includes cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.
As used herein xe2x80x9calkylcarbonylxe2x80x9d is intended to include an alkyl group of an indicated number of carbon atoms attached through a carbonyl group to the residue of the compound at the designated location. For example C1-C4 alkylcarbonyl includes methylcarbonyl, ethylcarbonyl, propylcarbonyl and butylcarbonyl.
As used herein xe2x80x9calkylcarbonyloxyxe2x80x9d is intended to include an alkyl group of an indicated number of carbon atoms attached to a carbonyl group, where the carbonyl group is attached through an oxygen atom to the residue of the compound at the designated location.
As used herein xe2x80x9calkylcarbonylaminoxe2x80x9d is intended to include an alkyl group of an indicated number of carbon atoms attached to a carbonyl group, where the carbonyl group is attached through an amino group to the residue of the compound at the designated location.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contain a basic or acidic moiety by conventional chemical methods. Generally, pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
It is understood that where the processes of the invention describe the use of a suitable acid to form an acid addition salt, one of skill in the art of synthesis can use an inorganic or an organic acid which could also render a pharmaceutically acceptable salt. In addition to the acids listed above for pharmaceutically acceptable salts the following acids are examples of suitable acids for the formation of an acid addition salt: phthalic acid, salicylic acid, isophthalic acid, and malonic acid.
As used herein, suitable recrystallization solvents include those in which the product will dissolve when heated and crystallize when cooled. Examples include, but are not limited to alkanes, ethers, esters (acetates), alcohols, aryls, halogenated alkanes, organic acids and water.
When any variable (for example, R10a, R3a, etc.) occurs more than one time in any constituent or formula for a compound, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R10a, then said group may optionally be substituted with up to three R10a and R10a at each occurrence is selected independently from the defined list of possible R10a. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture. Similarly, by way of example, for the group xe2x80x94C(R10a)2xe2x80x94, each of the two R10a substituents on C is independently selected from the defined list of possible R10a.
The compounds herein described may have asymmetric centers. All chiral, diastereomeric, and racemic forms are included in the present invention. It will be appreciated that certain compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound.
The present invention is contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
The following terms and abbreviations are used herein and defined as follows. The abbreviation: xe2x80x9cTHFxe2x80x9d as used herein means tetrahydrofuran, xe2x80x9cHPLCxe2x80x9d as used herein means high performance liquid chromatograpy, xe2x80x9cTLCxe2x80x9d as used herein means thin layer chromatography, xe2x80x9cliqxe2x80x9d as used herein means liquid, xe2x80x9cn-BuOHxe2x80x9d as used herein means n-butanol and xe2x80x9cTMEDAxe2x80x9d as used herein means N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine.
The methods of the present invention, by way of example and without limitation, may be further understood by reference to Scheme 1. Scheme 1 details the general synthetic method for the preparation of asymmetric cyclic ureas starting from monoacylation of a 1,4-diaminobutane. In Scheme 1, R10 is a substituted or unsubstituted benzyl group and G is a diol protecting group. 
Step 1: Monoacylation: Preparation of a Compound of Formula (II).
This step is conducted by reacting a diamine of formula (I) with an acylating agent, R1C(xe2x95x90O)R2, to form a monoacylated compound, (II), which can be used as is or can be reacted with a suitable acid to form an isolable acid addition salt. By way of general guidance, at least one equivalent, preferably one to two, more preferably 1.4 to 1.6 equivalents, of an acylating agent is added to a solution of compound (I) in a suitable solvent; while stirring at a suitable temperture the reaction is monitered for completion by HPLC analysis of reaction samples. Upon completion of the reaction, monoacylated compound, (II), can be isolated as a free base or as an acid addition salt by separation methods known to one skilled in the art. Separation methods and examples of standard work up are shown in Examples 1-8. Preferably, the free base is obtained by distilling off the acylating agent or the acid addition salt is obtained by addition of a suitable acid which results in precipitation of the acid addition salt. More preferably, the monoacylated compound, (II), is isolated as the phthalate salt from a mixture of toluene and isopropanol. The phthalic acid salt can be recrystallised from acetonitrile if further purification is required.
In Step 1 the reaction is considered complete by HPLC analysis when the ratio of the area percent product to area percent starting material is at least 10:1; preferably greater than 12:1; more preferably greater than 15:1.
Suitable solvents for the reaction of (I) with the acylating agent in step (1) are non-polar solvents such as toluene, methyl-t-butyl ether, cyclohexane, hexane, and heptane; most preferably toluene. The suitable acid in step (1) can be added neat, for example as a solid, as a suspension in a second solvent, or as a solution in a second solvent, selected by one of skill in the art; preferably an organic solvent miscible with the reaction solvent; more preferably isopropanol.
It is understood that a large scope of acylating agents, R1C(xe2x95x90O)R2, are suitable for this reaction. It is prefered that R2 is an alkoxy or phenoxy group, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, phenoxy, and equivalents thereof; and that R1 is a C1-C4 haloalkyl, preferably C1-C3 haloalkyl, such as CF3, CF2CF3, CF2CF2CF3, CF2Cl, CF2Br, CCl3, CBr3, or CH2F. More preferably the acylating agent is F3CC(xe2x95x90O)OCH2CH3.
A suitable temperature for the monoacylation reaction is from about 0xc2x0 C. to reflux of the solvent. The preferred temperature depends on the acylating agent, for example with F3CC(xe2x95x90O)OCH2CH3 the preferred range is 40-50xc2x0 C.; and is readily determined by one skilled in the art.
It is understood that one skilled in the art can determine the preferred reaction time of Step (1) as dependent on acylating agent and temperature of the reaction. For example with F3CC(xe2x95x90O)O(p-C6H4NO2) the reaction can be complete within 5 minutes at 0xc2x0 C. However, with Cl3CC(xe2x95x90O)OCH2CH3 the reaction was heated at 110xc2x0 C. for three days. Preferably the reaction is complete in less than twenty four hours; more preferably reaction is complete within 4-5 hours at 40-50xc2x0 C., for example when F3CC(xe2x95x90O)OCH2CH3 is the acylating agent.
Suitable acids for the preparation of the acid addition salt are phthalic acid, salicylic acid, isophthalic acid, malonic acid; preferably phthalic acid.
The reaction carried out in Step 1 has been run on various scales in kilo laboratory glassware and pilot plant scale.
Step 2: Reductive Amination: Preparation of a Compound of Formula (III).
This step is conducted by reacting an aldehyde of formula R7CH2CHO with a compound of formula (II) to form an imine which is subsequently reduced to a compound of formula (III) by a suitable reducing agent. By way of general guidance, compound (II) is dissolved in an organic solvent and neutralized by the addition of aqueous hydroxide solution (sodium or potassium) if the acid addition salt of (II) is used. The reaction is dried, for example by extraction and azeotropic distillation, afterwhich about one equivalent of R7CH2CHO is added to form the imine intermediate. Formation of the imine intermediate can be driven by additional drying of the reaction solvent by methods known to one skilled in the art, such as molecular sieves (for example 4 A sieves) or distillation, preferably via azeotropic removal of water. Subsequently, the imine is reduced by addition of a suitable reducing agent to form compound (III) which can be isolated by standard methods of work up. Examples of work up are given in Example 19, 19a, and 19b. It is optional that compound (III) can be isolated as an acid addition salt.
Suitable organic solvents for step 2 are toluene, cyclohexane, hexane, heptane, isopropyl acetate, and ethyl acetate; more preferably toluene.
The imine intermediate can be reduced to (III) with a variety of suitable reducing agents, such as, hydrogen metal catalysts, chemical reducing agents, and catalytic transfer hydrogenation.
For reductions using hydrogen preferred metal catalysts are Pd/C, Pt/C, Rh/C, and Raney-Nickel. Additionally, preferred solvents for reductions using hydrogen metal catalysts are methanol, ethanol, isopropanol, cyclohexane, toluene, tetrahydrofuran, ethyl acetate, isopropyl acetate or acetonitrile.
For reductions using chemical reducing agents preferred agents are sodium triacetoxy borohydride, sodium borohydride, pyridine/borane, lithium aluminium hydride, lithium borohydride, sodium cyanoborohydride, and sodium amalgam. Preferred solvents for reductions using chemical reducing agents are toluene, cyclohexane, methanol, ethanol, tetrahydrofuran and ether.
It is understood that one skilled in the art of organic synthesis will judiciously choose a suitable reducing agent based on the stability of R7 substituents on the aldehyde. For example, when R7 is propyl, it is more preferred that the reducing agent is 10% Pd/C in toluene. However, when R7 is phenyl, it is more preferred that the reducing agent is 5% Pt/C in methanol or ethanol between 25-45xc2x0 C. or sodium triacetoxy borohydride in toluene or cyclohexane between 25-45xc2x0 C.
It is understood that the acid addition salt of (III), if prepared, can be prepared from a number of suitable acids known to and judiciously chosen by one skilled in the art. Preferred acids are para-toluene sulphonic acid or methanesulfonic acid. For example, when R7 is phenyl, para-toluene sulphonic acid is preferred; and when R7 is propyl, methane sulphonic acid is preferred. Additionally, the acid addition salt of (III) can be prepared in a number of solvents; preferred solvents include ethyl acetate, isopropyl acetate or a mixture of cyclohexane and isopropanol.
The reaction carried out in Step 2 has been run on a kilogram scale.
Step 3: De-acylation: Preparation of a Compound of Formula (IV).
This step is conducted by reacting a compound of formula (III) as prepared in Step 2 with a suitable hydrolyzing agent under forcing conditions to form the primary amine compound of formula (IV). By way of general guidance, the protecting group is removed by hydrolysis wherein hydroxide ion in an alcohol solvent is preferred under refluxing conditions. Compound (IV) can be isolated or carried forward into Step 4.
Preferred hydrolyzing agents are sources of hydroxide ion in an alcohol solvent and include sodium hydroxide in methanol, potassium hydroxide in isopropanol and potassium hydroxide in n-butanol. A more preferable condition is isopropanol with 4 equivalents of potassium hydroxide at reflux.
Step 4: Reductive Amination: Preparation of a Compound of Formula (V).
This step is conducted by reacting 3-nitrile, 4-fluoro benzaldehyde with a compound of formula (IV) to form an imine which is subsequently reduced by a suitable reducing agent to form a compound of formula (V); as similarly described in Step 2. By way of general guidance, about one equivalent of 3-nitrile, 4-fluoro benzaldehyde is contacted with a compound of formula (IV) to form an imine intermediate, wherein azeotropic distillation of the water formed is preferred. The imine formed is contacted with a about 1 to about 3 equivalents of a suitable reducing agent, preferably a chemical reducing agent, more preferably sodium triacetoxy borohydride in toluene or cyclohexane between 25-45xc2x0 C. to form a compound of formula (V). The product can be isolated by standard methods of work up as shown in Example 20 and 20a. It is preferred that the compound of formula (V) is isolated and purified by recrystalising from n-heptane, hexane(s) or cyclohexane; more preferably n-heptane.
The reaction carried out in Step 4 has been run on a kilogram scale.
Step 5: Cyclization: Preparation of a Compound of Formula (VI).
This step is conducted by reacting a diamine compound of formula (V) with a cyclizing agent in the presence of a suitable base to form a compound of formula (VI). By way of general guidance a diamine compound of formula (V) and about 1.2 to about 3.0 equivalents, preferably 1.2 to 2.0 equivalents, of a suitable base are dissolved under reflux into a suitable solvent. About 0.4 to about 3.0 equivalents of cyclizing agent, depending on the equivalents of base, dissolved into the same suitable solvent are added subsurface, over a controlled period of time, to the refluxing mixture of compound (V) and base. During the addition of cyclizing agent the total volume of refluxing solution may be controlled by distilling off the solvent such that the maximum volume of refluxing solution is about 0.10 molar to about 0.13 molar, preferably 0.11 to 0.12 molar, in relation to compound (V). Upon complete addition of the cyclizing agent the reaction is cooled, the base-HCl salt formed removed, preferably by filtration or extraction, and the product compound (VI) isolated. Examples of workup are shown in Examples 22 and 22a.
Optionally, the cyclic urea (VI) can either be isolated and then deprotected, or subjected in situ to acidic conditions to remove the protecting group G to form compounds of Formula (VII). Methanolic hydrochloric acid or sulphuric acid is preferred to remove the diol protecting group G to form the free diol; whereupon the free diol generally crystallizes from the reaction mixture or can be isolated by methods known to one skilled in the art. Preferably, the protecting group G is acetonide.
The base is used to scavenge hydrochloric acid that is generated during the reaction and generally a non nucleophilic or weakly nucleophilic base can be used. Preferred suitable bases include N,N-diisopropylethylamine, triethylamine, N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine, N,N-dimethyloctylamine, tris(hydroxymethyl)aminomethane, and 1,8-bis(dimethylamino)napthalene. More preferable is N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylenediamine or tris(hydroxymethyl)aminomethane as the base. Most preferrable is tris(hydroxymethyl)aminomethane.
A suitable aprotic solvent for this step includes: benzene, cyclohexane, pentane, hexane, toluene, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, naphthalene, tetramethylurea, nitromethane, nitrobenzene, dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, t-butyl methyl ether, carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene, o-dichlorobenzene, chlorobenzene, or fluorobenzene.
Preferred solvents for step 5 include toluene, cyclohexane, chlorobenzene, 1,2-dichlorobenzene, and anisole. The more preferred solvent is toluene.
Preferred cyclizing agents for Step 5 are phosgene, diphosgene, and triphosgene; more preferred is 1.0-3.0 equivalents phosgene and about 0.4-0.6 equivalents of triphosgene; most preferred is 1.2-2.0 equivalents of phosgene.
The reaction carried out in Step 5 has been run on a kilogram scale.
Step 6: Preparation of Compounds of Formula (X); Amino Indazolyl Formation and Alcohol Deprotection.
This step is conducted by reacting a compound of formula (VI) or (VII) with hydrazine or a hydrazine equivalent in the presence of a base, such base being suitable for scavenging HF produced in the reaction, to form an amino indazolyl derivative of a compound of formula (VI) or (VII). Amino indazolyl derivatives of a compound of formula (VI) have an alcohol protecting group G which can be removed by conditions described in Step 5 above, ie acidic conditions, to form a compound of formula (X). Amino indazolyl derivatives of a compound of formula (VII) have already been alcohol deprotected as described by conditions in Step 5 above, ie acidic conditions, and therefore form a compound of formula (X) upon reaction with hydrazine or a hydrazine equivalent. By way of general guidance one equivalent of a compound of formula (VI) or (VII) is reacted with at least one equivalent to an excess, preferably at least two equivalents, more preferably at least five equivalents of hydrazine or a hydrazine equivalent in the presence of an HF scavenging base. Examples are shown in Examples 23 and 23a.
Bases suitable for scavenging HF are inorganic as well as organic bases. Preferred bases are carbonate salts such as potassium carbonate, cesium carbonate, and calcium carbonate. A more preferred base used to scavenge hydrofluoric acid is calcium carbonate. Optionally, hydrazine itself may function as the base to scavenge HF produced.
A suitable solvent for this step includes: low molecular weight alcohols, such as ethanol, propanol, butanol, pentanol, and hexanol; and ethers, such as tetrahydrofuran. Preferred is 2-propanol or n-butanol. Optionally, hydrazine itself may function as the solvent.
Hydrazine equivalents for this step include anhydrous hydrazine, hydrazine hydrate, and salts of hydrazine, such as hydrazine acetate, hydrazine bromide, hydrazine hydrochloride, and hydrazine sulfate. It is understood by one skilled in the art that when hydrazine salts are used an additional quantity of base must be used to neutralize the acid of the hydrazine salt. Preferred is hydrazine hydrate.
The reaction carried out in Step 6 has been run on a kilogram scale.
The present invention, by way of example and without limitation, may be further exemplified by reference to Scheme 2. 
Step 1A: Bis-acylation: Preparation of a Compound of Formula (XI).
This step is conducted by reacting a diamine compound of formula (I) with an excess of a strongly electrophilic acylating agent (VIII) in the presence of a base to give a bis-acylated compound of formula (XI). By way of general guidance, to a solution of a diamine of formula (I) and about 3 equivalents base is slowly added an excess, preferably about 2 to about 5, more preferably about 2.5 equivalents of a strongly electrohphilic acylating agent while controlling the temperature. It is understood that one skilled in the art can determine the rate of addition as dependent on acylating agent and maintaining a preferred temperature of the reaction between about 0 to about 35xc2x0 C. After addition of the acylating agent the reaction is aged for a sufficient amount of time, preferably about 30 minutes to about 24 hours, more preferably about 1 hour to about 3 hours, at a temperature of about 0xc2x0 C. to reflux to form the bis-acylated compound (XI). The preferred temperature depends on which acylating agent is used, preferably the acylating agent is CF3(CO)O(CO)CF3 wherein the preferred temperature range is about 0 to about 35xc2x0 C. The product (XI) may be separated from the reaction as a stable solid by standard methods of workup, an example of which is shown in Example 17.
It is understood that a large scope of strongly electrophilic acylating agents are suitable for this reaction, such as anhydrides, R1(CO)O(CO)R1, or R1 substituted acid halides, eg. R1C(xe2x95x90O)Cl. It is preferred that R1 is a C1-C3 haloalkyl, such as CF3, CF2CF3, CF2CF2CF3, CF2Cl, CF2Br, CCl3, CBr3, or CH2F. More preferably the acylating agent is CF3(CO)O(CO)CF3.
Preferred solvents for Step 1A include toluene, cyclohexane, hexane, heptane, methyl t-butyl ether, tetrahydrofuran, acetonitrile, water or mixtures of any of these solvents and water. Most preferably toluene.
In Step 1A, it is understood that a wide range of bases are suitable. Preferred bases include trialkylamines, pyridine, and inorganic bases; more preferably triethylamine, pyridine, sodium hydroxide, or potassium carbonate; most preferably triethylamine.
Step 1B: Mono-deacylation: Preparation of a Compound of Formula (II).
This step is conducted by reacting a diacyl diamine of formula (XI) with a suitable base to form a compound of formula (II). By way of general guidance, a diacyl diamine of formula (XI) is reacted with about 1 to 3, preferably about 1 to 2, more preferably about 1.0 to about 1.2 equivalents of a suitable base in a suitable solvent at a suitable temperature for a sufficient amount of time and subsequently quenched with about 1.0 to about 1.2 equivalents of a quenching acid, preferably acetic acid, to form the monoacylated derivative (II). Compound (II) can be used as is or can be reacted with an acid to form a suitable isolable acid addition salt. An example of workup is shown in Example 18.
Preferred acids in Step 1B for the preparation of an isolable acid addition salt include phthalic acid, salicylic acid, isophthalic acid, and malonic acid; more preferrable the acid is phthalic acid. When R1 is CF3 the product is preferably isolated as the phthalate salt from a mixture of toluene and isopropanol.
A preferrable advantage to preparation of isolable acid addition salts is the further utilization of this step as a purification procedure. For example, the phthalic acid salt of (II) can be recrystallised from acetonitrile if further purification is required.
In Step 1B many suitable bases can be utilized as a suitable source of hydroxide ion such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, magnesium hydroxide, potassium carbonate and water. Additional bases include a C1-C10 alkoxide salt of sodium, potassium, or lithium, in the presence of water; for example sodium methoxide and water, sodium ethoxide and water, potassium tert-butoxide and water; as well as n-butyl lithium and water. Preferably a mixture of potassium tert-butoxide and water.
A number of solvents can be used such as 2-propanol, ethanol, methanol, tetrahydrofuran, toluene, methyl t-butyl ether, cyclohexane, hexane, heptane, acetonitrile, mixtures thereof or mixtures thereof with water. More preferable is a mixture of tetrahydrofuran/methanol/water or tetrahydrofuran/methanol; most preferable is a mixture of tetrahydrofuran/methanol/water.
A suitable temperature for the mono-deacylation reaction is from about 0xc2x0 C. to reflux of the solvent. The preferred temperature depends on R1 and is readily determined by one skilled in the art. For example, when R1 is CF3 the preferred range in THF/methanol/water is about 58 to about 64xc2x0 C.
It is understood that a compound of formula (II) can be synthesized from a large scope of acylating agents. It is prefered that R1 in Step 1B is a C1-C4 haloalkyl, preferably C1-C3 haloalkyl, such as CF3, CF2CF3, CF2CF2CF3, CF2Cl, CF2Br, CCl3, CBr3, or CH2F. More preferably R1 is CF3.
The following examples are meant to be illustrative of the present invention. These examples are presented to exemplify the invention and are not to be construed as limiting the inventor""s scope.
Starting materials, alkylating agents and reagents of the invention can be obtained commercially or prepared in a number of ways well known to one skilled in the art of organic synthesis. The starting materials and alkylating agents of the invention can be synthesized using the methods described in U.S. Pat. No. 5,532,356, U.S. Pat. No. 5,610,294, U.S. Pat. No. 5,530,124, U.S. Pat. No. 5,532,357, U.S. Pat. No. 5,559,252, and U.S. Pat. No. 5,637,780, the disclosures of which are hereby incorporated by reference. Where the above references describe alkylating agents that are benzyl halides or alkyl halides or the like, it is understood that one skilled in the art of organic synthesis can readily oxidize the halide to an aldehyde by methods known in the art.
As described herein, HPLC conditions for the determination of starting materials, products and intermediates in Step (1) are: Column: Waters Symmetry-C18, 150xc3x973.9 mm, 5 xcexcm; flow rate: 1.5 ml/minute; injection volume: 5 microliters; wavelength: 220 nm; Oven temperature: 40xc2x0 C.; Solvent A: 5 mM sodium dihydrogen phosphate and 5 mM diammonium hydrogen phosphate in water; Solvent B: acetonitrile; gradient timetable for solvents: T=0 minutes 65:35 A:B; T=12 minutes 30:70 A:B; T=15 minutes 15:85 A:B.